This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The progression of drug addiction in humans typically involves a transition from casual, recreational drug use to compulsive drug use that leads to serious adverse consequences. Hence, the frequency and pattern of drug use changes as a function of drug history. This project utilized i.v. drug self-administration protocols in rhesus monkeys to identify behavioral and neurochemical endpoints indicative of transitional states in drug addiction. This project focused on changes in behavior and neurochemistry as subjects undergo an extensive history of cocaine self-administration. Reinstatement (relapse) effects of cocaine were remarkably stable even in subjects with an extensive history of cocaine use. Moreover, rhesus monkeys did not escalate their pattern of drug intake when given extended access to cocaine, as reported in rodent studies. However, there was clear tolerance that developed to cocaine- and amphetamine-induced increases in dopamine associated with a prolonged history of cocaine use. These results document obvious species differences and highlight the importance of the nonhuman primate model employed. Also, PET imaging with FDG has shown an enhancement in cocaine-induced brain metabolic effects that may link behavior with neurocircuitry. Brain tissue obtained from the last group of subjects has been sent to our colleague at Wake Forest University to assay changes in gene expression as a function of cocaine history. The primary gene targets have emphasized components of the dopamine and glutamate systems.